Discovery of potent aryl-substituted 3-[(3-methylpyridine-2-carbonyl) amino]-2,4-dimethyl-benzoic acid EP4 antagonists with improved pharmacokinetic profile

  • Bioorg Med Chem Lett. 2016 Feb 1;26(3):931-935. doi: 10.1016/j.bmcl.2015.12.057.
Maria-Jesus Blanco  1 ,  Tatiana Vetman  2 ,  Srinivasan Chandrasekhar  2 ,  Matthew J Fisher  2 ,  Anita Harvey  2 ,  Mark Chambers  2 ,  Chaohua Lin  2 ,  Daniel Mudra  2 ,  Jennifer Oskins  2 ,  Xu-Shan Wang  2 ,  Xiao-Peng Yu  2 ,  Alan M Warshawsky  2
Affiliations
  • 1. Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN 46285, United States. Electronic address: [email protected].
  • 2. Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN 46285, United States.
PMID: 26764191 DOI: 10.1016/j.bmcl.2015.12.057
Abstract

Two new series of EP4 antagonists containing a 3-methylaryl-2-carbonyl core have been identified. One series has a 3-substituted-phenyl core, while the other one incorporates a 3-substituted pyridine. Both series led to compounds with potent activity in functional and human whole blood (hWB) assays. In the pyridine series, compound 7a was found to be a highly potent and selective EP4 antagonist, with suitable rat and dog pharmacokinetic profiles.

Keywords
EP4 receptor antagonist; Human whole blood (hWB) assay; Inflammation; Pain; Prostaglandin E2; Structure–activity relationship (SAR).